N2003-01: Irinotecan, Temozolomide, and Cefixime in Treating Young Patients With Recurrent or Resistant Neuroblastoma

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RATIONALE: Drugs used in chemotherapy, such as irinotecan and temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Temozolomide may help irinotecan kill more tumor cells by making them more sensitive to the drug. Cefixime may be effective in preventing diarrhea that is caused by treatment with irinotecan.

PURPOSE: This phase I trial is studying the side effects and best dose of irinotecan when given together with temozolomide and cefixime in treating young patients with recurrent or resistant neuroblastoma.

Condition or disease

Intervention/treatment

Phase

DiarrheaDrug/Agent Toxicity by Tissue/OrganNeuroblastoma

Drug: cefiximeDrug: irinotecan hydrochlorideDrug: temozolomide

Phase 1

Detailed Description:

OBJECTIVES:

Primary

Determine the maximum tolerated dose of oral irinotecan when administered with fixed-dose temozolomide and cefixime in pediatric patients with recurrent or resistant high-risk neuroblastoma.

Determine the toxic effects of this regimen in these patients.

Secondary

Determine the response rate in patients treated with this regimen.

Determine the pharmacokinetics of this regimen in these patients.

Correlate UGT1A1 genotype with the occurrence of dose-limiting diarrhea in patients treated with this regimen.

Correlate BCRP genotype with pharmacokinetic phenotype in patients treated with this regimen.

Correlate p53 status in tumor cells with response in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of irinotecan.

Patients receive oral cefixime once daily beginning 5 days before the start of fixed-dose temozolomide and irinotecan and continuing for the duration of the study. Patients also receive oral temozolomide once daily on days 1-5 and oral irinotecan once daily on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of irinotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A maximum of 12 patients are treated at the MTD.

Patients are followed for toxicity, response, and survival.

PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for this study within 1.25 years.

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At least 1 site with positive uptake by metaiodobenzylguanidine (MIBG) scan*

Bone marrow with tumor cells seen on routine morphology (not by NSE staining only) of bilateral aspirate AND/OR biopsy on 1 bone marrow sample NOTE: *Patients who never experienced disease recurrence or progression must demonstrate viable neuroblastoma in a biopsy of either bone marrow or bone and/or soft tissue site (biopsy must be performed ≥ 4 weeks after completion of prior radiotherapy if lesion was irradiated)

PATIENT CHARACTERISTICS:

Age

1 to 30 at diagnosis

Performance status

ECOG 0-2

Life expectancy

At least 2 months

Hematopoietic

Absolute neutrophil count ≥ 750/mm^3

Platelet count ≥ 75,000/mm^3 (without transfusion)

Hemoglobin ≥ 8.0 g/dL (transfusion allowed)

Hepatic

SGPT and SGOT < 5 times normal

Bilirubin ≤ 1.5 times normal

Renal

Creatinine ≤ 1.5 times normal for age

No greater than 0.8 mg/dL (≤ 5 years of age)

No greater than 1.0 mg/dL (6 to 10 years of age)

No greater than 1.2 mg/dL (11 to 15 years of age)

No greater than 1.5 mg/dL (> 15 years of age)

Other

Not pregnant or nursing

Negative pregnancy test

Fertile patients must use effective contraception

No allergy to cephalosporins

No active diarrhea

No uncontrolled infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

See Chemotherapy

Recovered from prior immunotherapy

More than 3 weeks since prior biologic therapy and recovered

More than 2 days since prior hematopoietic growth factors

No concurrent epoetin alfa

No concurrent prophylactic hematopoietic growth factors during the first treatment course

No concurrent immunomodulating agents except steroids to control intracranial pressure